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Targeting the 5-HT1B-YAP positive feedback loop protects against disturbed flow-induced atherogenesis in mice

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Atherosclerosis preferentially develops at arterial bifurcations where the endothelial cells are constantly exposed to disturbed flow, and sustained oscillatory shear stress (OSS) triggers endothelial inflammation. The mechanosensitive transcriptional coactivator YAP plays a critical role in disturbed flow-induced endothelial inflammation. Our recent studies show that disturbed flow upregulates the expression of the mechanosensor 5-HT1B. In this study, we investigated the molecular mechanisms underlying OSS-induced 5-HT1B upregulation in vivo and in vitro. Disturbed flow was induced in mice by partial carotid ligation. In vitro experiments were conducted in human aortic endothelial cells (HAECs) subjected to oscillatory shear stress using an ibidi flow system. We showed that oscillatory shear stress significantly upregulated the expression of 5-HT1B in HAECs via activation of YAP, while knockout of YAP significantly reduced this upregulation. We demonstrated that YAP directly regulated the expression of HTR1B via binding to its promoter region. Inhibition of 5-HT1B using its antagonist SB-216641 impeded YAP nuclear localization and endothelial activation in HAECs. We verified that a 5-HT1B-YAP loop was also activated in atherosclerotic arteries of ApoE−/− mice. Endothelium-specific overexpression of YAP exacerbated atherosclerosis. Moreover, endothelium-specific knockout of 5-HT1B or YAP inhibited disturbed flow-induced endothelial inflammation and plaque formation in ApoE−/− mice. Taken together, the 5-HT1B-YAP positive feedback loop amplifies the pro-atherogenic effect of disturbed flow. We suggest that targeting 5-HT1B-YAP loop holds promise as a novel therapeutic strategy for atherosclerotic diseases.

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Fig. 1: Oscillatory shear stress upregulates the expression of 5-HT1B via activation of YAP.
Fig. 2: YAP regulates the expression of HTR1B via binding to the promoter.
Fig. 3: Inhibition of 5-HT1B impedes YAP nuclear localization and endothelial activation.
Fig. 4: The 5-HT1B-YAP loop is activated in atherosclerotic arteries of ApoE−/− mice.
Fig. 5: Endothelium-specific overexpression of YAP promotes atherosclerosis.
Fig. 6: Targeting the 5-HT1B-YAP loop inhibits disturbed flow-induced endothelial inflammation and plaque formation.
Fig. 7: Schematic overview of 5-HT1B-YAP positive loop enhancing the pro-atherogenic effects of disturbed flow.

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References

  1. Mensah GA, Fuster V, Murray CJL, Roth GA. Global burden of cardiovascular diseases and risks, 1990-2022. J Am Coll Cardiol. 2023;82:2350–473.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Luo Y, Liu J, Zeng J, Pan H. Global burden of cardiovascular diseases attributed to low physical activity: an analysis of 204 countries and territories between 1990 and 2019. Am J Prev Cardiol. 2024;17:100633.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Davis MJ, Earley S, Li YS, Chien S. Vascular mechanotransduction. Physiol Rev. 2023;103:1247–421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Prim. 2019;5:56.

    Article  PubMed  Google Scholar 

  5. Cheng CK, Wang N, Wang L, Huang Y. Biophysical and biochemical roles of shear stress on endothelium: a revisit and new insights. Circ Res. 2025;136:752–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Peng Z, Shu B, Zhang Y, Wang M. Endothelial response to pathophysiological stress. Arterioscler Thromb Vasc Biol. 2019;39:e233–e43.

    Article  CAS  PubMed  Google Scholar 

  7. Immanuel J, Yun S. Vascular inflammatory diseases and endothelial phenotypes. Cells. 2023;12:1640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bjorkegren JLM, Lusis AJ. Atherosclerosis: recent developments. Cell. 2022;185:1630–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mitrophanov AY, Groisman EA. Positive feedback in cellular control systems. Bioessays. 2008;30:542–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ratushny AV, Saleem RA, Sitko K, Ramsey SA, Aitchison JD. Asymmetric positive feedback loops reliably control biological responses. Mol Syst Biol. 2012;8:577.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Poston RN. Atherosclerosis: integration of its pathogenesis as a self-perpetuating propagating inflammation: a review. Cardiovasc Endocrinol Metab. 2019;8:51–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tasouli-Drakou V, Ogurek I, Shaikh T, Ringor M, DiCaro MV, Lei K. Atherosclerosis: a comprehensive review of molecular factors and mechanisms. Int J Mol Sci. 2025;26:1364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cui X, Wang Y, Li X, Li H, Yin R, Liu Y, et al. A positive feedback loop between CXCL16 and the inflammatory factors IL-17A and TGF-beta promotes large artery atherosclerosis by activating the STAT3/NF-kappaB pathway. Cardiovasc Ther. 2025;2025:2973633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Feaver RE, Gelfand BD, Wang C, Schwartz MA, Blackman BR. Atheroprone hemodynamics regulate fibronectin deposition to create positive feedback that sustains endothelial inflammation. Circ Res. 2010;106:1703–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xie Q, Li F, Shen K, Luo C, Song G. LOXL1-AS1/miR-515-5p/STAT3 positive feedback loop facilitates cell proliferation and migration in atherosclerosis. J Cardiovasc Pharmacol. 2020;76:151–8.

    Article  CAS  PubMed  Google Scholar 

  16. Kotla S, Zhang A, Imanishi M, Ko KA, Lin SH, Gi YJ, et al. Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation. Redox Biol. 2021;47:102132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. An T, Guo M, Fan C, Huang S, Liu H, Liu K, et al. sFgl2-Treg positive feedback pathway protects against atherosclerosis. Int J Mol Sci. 2023;24:2338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhu T, Mu BR, Li B, Ran Z, Wang DM, Zhou Y, et al. IGFBP7: a novel biomarker involved in a positive feedback loop with TGF-beta1 in idiopathic pulmonary fibrosis. Cell Signal. 2025;133:111867.

    Article  CAS  PubMed  Google Scholar 

  19. Chen H, Gong Y, Wu F, Wu M, Li S, Chen B, et al. WWP1-SHARP1-C/EBPbeta positive feedback loop modulates development of metabolic dysfunction-associated steatotic liver disease. Metabolism. 2025;169:156271.

    Article  CAS  PubMed  Google Scholar 

  20. Yang TT, Shao YT, Cheng Q, He YT, Qiu Z, Pan DD, et al. YY1/HIF-1alpha/mROS positive-feedback loop exacerbates glomerular mesangial cell proliferation in mouse early diabetic kidney disease. Acta Pharmacol Sin. 2025;46:1974–89.

    Article  CAS  PubMed  Google Scholar 

  21. Ku D, Yang Y, Park Y, Jang D, Lee N, Lee YK, et al. SLIRP amplifies antiviral signaling via positive feedback regulation and contributes to autoimmune diseases. Cell Rep. 2025;44:115588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Song Z, Gui S, Rao X, Zhang G, Cheng Y, Zeng T. TAZ/NRF2 positive feedback loop contributes to proliferation in bladder cancer through antagonistic ferroptosis. Cell Death Discov. 2025;11:208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang L, Luo JY, Li B, Tian XY, Chen LJ, Huang Y, et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature. 2016;540:579–82.

    Article  CAS  PubMed  Google Scholar 

  24. Wang KC, Yeh YT, Nguyen P, Limqueco E, Lopez J, Thorossian S, et al. Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis. Proc Natl Acad Sci USA. 2016;113:11525–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jiang M, Ding H, Huang Y, Lau CW, Guo Y, Luo J, et al. Endothelial serotonin receptor 1B acts as a mechanosensor to drive atherosclerosis. Circ Res. 2025;136:887–901.

    Article  CAS  PubMed  Google Scholar 

  26. Ding H, Jiang M, Chan AM, Xia Y, Ma RCW, Yao X, et al. Targeting the tyrosine kinase Src in endothelium attenuates inflammation and atherogenesis induced by disturbed flow. Br J Pharmacol. 2025;182:4861–75.

  27. Jiang MC, Ding HY, Huang YH, Cheng CK, Lau CW, Xia Y, et al. Thioridazine protects against disturbed flow-induced atherosclerosis by inhibiting RhoA/YAP-mediated endothelial inflammation. Acta Pharmacol Sin. 2023;44:1977–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ding H, Jiang M, Lau CW, Luo J, Chan AM, Wang L, et al. Curaxin CBL0137 inhibits endothelial inflammation and atherogenesis via suppression of the Src-YAP signalling axis. Br J Pharmacol. 2023;180:1168–85.

    Article  CAS  PubMed  Google Scholar 

  29. Varadi K, Michelfelder S, Korff T, Hecker M, Trepel M, Katus HA, et al. Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors. Gene Ther. 2012;19:800–9.

    Article  CAS  PubMed  Google Scholar 

  30. Zolotukhin S, Byrne BJ, Mason E, Zolotukhin I, Potter M, Chesnut K, et al. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Ther. 1999;6:973–85.

    Article  CAS  PubMed  Google Scholar 

  31. Grieger JC, Choi VW, Samulski RJ. Production and characterization of adeno-associated viral vectors. Nat Protoc. 2006;1:1412–28.

    Article  CAS  PubMed  Google Scholar 

  32. Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology joint committee on clinical practice guidelines. Circulation. 2023;148:e9–e119.

    Article  PubMed  Google Scholar 

  33. Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL 2nd, Goldstein LB, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019;39:e38–e81.

    Article  CAS  PubMed  Google Scholar 

  34. Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res. 2019;124:328–50.

    Article  CAS  PubMed  Google Scholar 

  35. Pereira NL, Cresci S, Angiolillo DJ, Batchelor W, Capers QT, Cavallari LH, et al. CYP2C19 genetic testing for oral P2Y12 inhibitor therapy: a scientific statement from the American Heart Association. Circulation. 2024;150:e129–e50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jin H, Song J, Shen X, Liang Q, Sun G, Yu Y. Multiple genetic mutations increase the risk of thrombosis associated with clopidogrel after percutaneous coronary intervention. Pharmacogenomics. 2023;24:227–37.

    Article  CAS  PubMed  Google Scholar 

  37. Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct Target Ther. 2022;7:131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–31.

    Article  CAS  PubMed  Google Scholar 

  39. Woxholt S, Ueland T, Aukrust P, Anstensrud AK, Broch K, Tollefsen IM, et al. Effect of tocilizumab on endothelial and platelet-derived CXC-chemokines and their association with inflammation and myocardial injury in STEMI patients undergoing primary PCI. Int J Cardiol. 2025;418:132613.

    Article  PubMed  Google Scholar 

  40. Schmitt C, Abt M, Ciorciaro C, Kling D, Jamois C, Schick E, et al. First-in-Man study with Inclacumab, a human monoclonal antibody against P-selectin. J Cardiovasc Pharmacol. 2015;65:611–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jiang M, Ding H, Huang Y, Wang L. Shear stress and metabolic disorders-two sides of the same plaque. Antioxid Redox Signal. 2022;37:820–41.

    Article  CAS  PubMed  Google Scholar 

  42. Wang Y, Sun Y, Zhao W, Zhang J, Wang X, Hu F, et al. Regulatory mechanisms of the Hippo/YAP axis by G-protein coupled estrogen receptor in gastric signet-ring cell carcinoma. Neoplasia. 2025;67:101199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ong YT, Andrade J, Armbruster M, Shi C, Castro M, Costa ASH, et al. A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth. Nat Metab. 2022;4:672–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rauluseviciute I, Riudavets-Puig R, Blanc-Mathieu R, Castro-Mondragon JA, Ferenc K, Kumar V, et al. JASPAR 2024: 20th anniversary of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 2024;52:D174–D82.

    Article  CAS  PubMed  Google Scholar 

  45. Abramson J, Adler J, Dunger J, Evans R, Green T, Pritzel A, et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature. 2024;630:493–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Alhosaini K, Azhar A, Alonazi A, Al-Zoghaibi F. GPCRs: the most promiscuous druggable receptor of the mankind. Saudi Pharm J. 2021;29:539–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by Hong Kong Research Grants Council grants (T12-101/23-N, SRFS2021-4S04, AoE/M-401/24-R, and 11103222), National Natural Science Foundation of China (91939302), and Hong Kong Health and Medical Research Fund (07181286). The schematic diagrams were prepared using BioRender.

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Author notes

  1. These authors contributed equally: Min-chun Jiang, Huan-yu Ding.

Authors and Affiliations

  1. Department of Endocrinology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China

    Min-chun Jiang, Hai-xia Guan & Jian Kuang

  2. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China

    Min-chun Jiang, Huan-yu Ding, Yin Xia & Xiao-qiang Yao

  3. Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong, 999077, China

    Chak Kwong Cheng, Li Wang & Yu Huang

  4. School of Medicine, South China University of Technology, Guangzhou, 510006, China

    Dong-qin Cai

  5. Department of Cardiovascular, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangzhou, 510080, China

    Dong-qin Cai

  6. Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China

    Ronald Ching Wan Ma

  7. Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, 999077, China

    Yu Huang

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Contributions

MCJ, HYD, and YH designed the study. MCJ and HYD conducted experiments and collected data. MCJ, HYD, CKC, DQC, and LW analyzed the data. MCJ, HYD, and YH drafted the manuscript. HXG, JK, RCWM, YX, and XQY provided constructive suggestions in experimental design and helped revise the article. YH, YX, and RCWM provided funds. YH is the leading principal investigator who directed the study. All authors revised and approved the final version of the manuscript.

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Correspondence to Yu Huang.

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Jiang, Mc., Ding, Hy., Cheng, C.K. et al. Targeting the 5-HT1B-YAP positive feedback loop protects against disturbed flow-induced atherogenesis in mice. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01672-x

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